Exposed vets had double the risk of MGUS

Action Points

Note that this observational cohort study identified an association between Agent Orange exposure and subsequent MGUS.

Be aware that the precise component (or components) of Agent Orange that might predispose to this condition are not known.

Veterans exposed to the powerful and toxic defoliant Agent Orange during the Vietnam War have a significantly increased risk of the precursor state for multiple myeloma, a prospective cohort study now shows.

Exposure to Agent Orange doubled the risk of monoclonal gammopathy of undetermined significance (MGUS), as compared with veterans who were not exposed. The herbicide was used from 1962 to 1972 to destroy vast stretches of jungle canopy, missions known collectively as Operation Ranch Hand.

Agent Orange contained several herbicides, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a known human carcinogen, as reported online in JAMA Oncology by Ola Landgren, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and co-authors.

"To our knowledge, our findings provide the first direct scientific evidence for an association between the multiple myeloma precursor, MGUS, and exposure to Agent Orange/TCDD among (Operation) Ranch Hand veterans," the authors wrote.

"Our observations are important in that they add support to a previous finding that certain pesticides play a role in the development of MGUS," they added.

The data also showed a trend toward an association between increased body burden of Agent Orange and MGUS.

The study involved serum specimens and exposure data collected in 2002 as part of the Air Force Health Study (AFHS). Investigators compared specimens from 479 former USAF personnel who participated in Operation Ranch Hand and 479 other personnel who served in Southeast Asia during the same time period but who were not involved in the missions.

The Ranch Hand veterans and the comparison veterans had similar demographic and lifestyle characteristics as well as medical histories, noted the investigators. The study population's median age in 2002.

The results showed an MGUS prevalence of 7.1% (34 of 479) in Ranch Hand veterans as compared with 3.1% (15 of 479) in comparison veterans.

"The cohort status was significantly (P<0.001) associated with TCDD levels from the 1987 reference year," wrote the authors. "This was illustrated most obviously by the increased percentage of men with TCDD levels greater than 10.92 ppt in the Ranch Hand veterans (47.5%) relative to those in the comparison veterans (2.5%)."

Investigators were unable to assess the independent effects of TCDD in relation to MGUS risk. Because of that limitation and others, "we cannot discriminate among the phenoxy herbicides, the TCDD contaminant, or other cohort factors as the underlying cause of the increased prevalence of MGUS in Ranch Hand veterans," said Landgren.

In an accompanying editorial, Nikhil C. Munshi, MD, of VA Boston Healthcare System and Dana-Farber Cancer Institute, in Boston, noted that the study "now provides further evidence of an association between Agent Orange exposure and development of plasma cell disorder."

"Although this study associated risk of MGUS with Agent Orange exposure, the fact that all multiple myeloma cases originate from MGUS provides the first scientific evidence for a direct link between multiple myeloma and Agent Orange exposure," Munshi wrote.

Munshi pointed out that the Institute of Medicine has identified a predisposition to seven types of malignant neoplasms in veterans exposed to Agent Orange. Four of these, including the one reported by Landgren et al, are B-cell lymphoid neoplasms.

It is interesting to note, said Munshi, that almost 25% of the comparison veterans had TCDD levels greater than 5.81 per trillion from unclear exposure. "Future studies may need to focus on such unknown exposures, which hopefully have significantly declined with tighter environmental controls in the United States."

It will also be important to investigate in other countries, where less stringent regulations may have resulted in populations receiving higher chemical exposures, he said.

The study is probably the first systematic effort to address the potential associations between Agent Orange and markers of multiple myeloma, commented Shaji Kumar, MD, of the Mayo Clinic, Rochester, MN. "This evidence is about as good as you can get, short of a large prospective study to address this question," he said in an interview.

Despite the long follow-up period in the study, investigators could not ascertain which patients with MGUS subsequently developed multiple myeloma. "This is a major drawback of the study," Kumar told MedPage Today.

"We don't know if this population developed MGUS because of Agent Orange exposure and if they have the same risk of developing multiple myeloma as people who develop MGUS in the general population."

"While the study adds to the overall evidence, it doesn't answer the question of whether or not being more susceptible leads to more cancer," Kumar added. "The median age of myeloma generally is 67 years but we don't know how many of the veterans developed multiple myeloma or the mechanism for that."

Additionally, the study included no women, and African-Americans, known to have a 3-4-fold increased risk of MGUS and myeloma, accounted for only about 5% of each group.

Finally, the study showed a higher-than-expected prevalence of abnormal free light-chain MGUS (LC-MGUS), which is less likely to progress to multiple myeloma, Kumar noted.

This study was supported by the Intramural Program at the Agency for Toxic Substances and Disease Registry, the Intramural Program at the National Cancer Institute, and the Air Force Health Study (AFHS) Assets Research Program at the Institute of Medicine through an award to the Centers for Disease Control and Prevention (CDC) Foundation.

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